Sitaxsentan (Thelin®), (2-[2-(6-methyl-benzo[1,3]dioxol-5-yl)-acetyl]-thiophene-3-sulfonic acid (4-chloro-3-methyl-isoxazol-5-yl)-amide) is a purported selective endothelin receptor A (ETA) antagonist that is approved by the Food and Drug Administration for the treatment of hypertension and heart failure. Sitaxsentan, the first ETA-selective EMA-approved member of this mechanistic class, blocks the binding of the neurohormone endothelin-1 (ET-1) to ETA. TBC3711 (3-(3,4-dimethyl-isoxazol-5-ylsulfamoyl)-thiophene-2-carboxylic acid (2-acetyl-4,6-dimethyl-phenyl)-amide), another member of this class, is currently undergoing clinical trials (O'Callaghan et al., International Journal of Clinical Practice 2006, 60(4), 475-481; Souza et al., International Journal of Clinical Practice 2007, 61(1), 153-156; Wu et al., Journal of Medicinal Chemistry 1999, 42(22), 4485-4499).

A common and severe side effect of sitaxsentan administration is hepatotoxicity. This hepatotoxicity is likely related to sixaxsentan's metablolism. The methylenedioxy moiety of sitaxsentan is a potential site of oxidative metabolism, which can undergo further biotransformations to form a reactive electrophilic metabolite. This electrophic metabolite could then account for the hepatotoxicity. Sitaxsentan is also known to significantly inhibit CYP2C9, one of the enzymes responsible for its oxidative transformation in vivo. Accordingly, sitaxsentan may cause undesirable drug-drug interactions when coadministered with other medications.